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Value of Cytogenetic Investigation in the Diagnosis of Dysmorphic Syndromes
1 Department of Medical Genetics
2 Pediatric Clinic III
Victor Babes University of Medicine & Pharmacy Timisoara

Correspondence to:
Olimpia Tudose, MD, Ph. D
Department of Medical Genetics
E. Murgu St. 2
Victor Babes University of Medicine & Pharmacy
1900 Timisoara
Tel: +40256204476
We report three patients with dysmorphic features, in whom the cytogenetic investigation revealed some chromosomal abnormalities. One of the patients presented microcephaly, facial dysmorphism and severe muscular hypotonia. The other one had brachycephaly, and psychomotor retardation. The clinical picture in the third one included microcephaly, facial dysmorphism, congenital heart defect, muscular hypotonia and foot deformity. In these patients analysis of GTG-banded chromosomes showed the following structural chromosomal abnormalities: del (18) (p11.31-11.32), del (16) (q12.23-12.24) and 15p+, respectively. Our study suggests the correlation between the structural abnormalities and the clinical picture.

The structural chromosomal abnormalities occur with very high frequency in the human population.
Partial monosomy 18p- or the deletion of the short arm of chromosome 18 is one of the most frequently occurring chromosomal aberration with minimal abnormalities at birth, which become more apparent at about 3 years of age. The phenotype varies from case to case. The symptoms frequently found in these patients are brachycephaly, holoprosencephaly, abnormalities of the ears, eyes, nose mouth and oral structures, muscular hypotonia, hand abnormalities, growth and mental retardation, but many other systems may also be affected. The phenotype usually reflects the length and type of deletion. Most studies discovered few critical regions for the 18p- syndrome, which lie on the p arms of chromosome 18 and they confer susceptibility for the various clinical manifestations.
Chromosome 16q deletion syndrome is mainly characterized by developmental delay, craniofacial anomalies, hypotonia, failure to thrive, feeding difficulties, mental retardation. The phenotype may be milder if the deletion involves more distal regions from 16q to 16q24.1, but deletions in regions q24.2 and q24.3 are believed to be lethal. There are only few reported chromosomal aberrations of chromosome 16, which were discovered and described in infants with dysmorphic features.
The pericentromeres and the entire p arms of the acrocentric chromosomes from group D are almost unknown and between the most uncharacterized regions of the human genome (1).


Patient 1 is a 3-1 years old girl referred for cytogenetic investigation because the physical examination showed brachycephaly, ocular hypertelorism, broad nose, low-set ears, down turned corners of the mouth and psychomotor retardation. The second patient presented at birth microcephaly, up slanting palpebral fissures, blepharoptosis, ocular hypertelorism, large and low-set ears, broad nose. The third patient we investigated was born premature at 32 weeks of pregnancy, birthweight 1900g, with multiple anomalies: facial dysmorphism, microcephaly, dolichocephaly, and congenital heart defect with cyanosis, muscular hypotonia and left foot deformity.

Chromosomal analysis at each patient was carried out on peripheral lymphocytes. GTG-banding was performed according to standard procedures. The cytogenetic analysis revealed structural chromosomal aberrations in all patients. Thus, patient 1 had the following abnormality in the karyotype: del (18) (p11.31-11.32). In patient 2 a deletion involving the long arm of chromosome 16 was found in all examined metaphases, thus the karyotype was: 46, XX, del (16)(q12.23-12.24). The third patient had extra genetic material on the short arms of chromosome 15, but using only G-banding technique we could not establish its origin.


As chromosomal anomalies involve either the presence of extra genetic material or deletion of the genetic material, the vast majority of these aberrations is lethal and frequently results in spontaneous abortion. Over half of these are involved in miscarriages. Thus, chromosomal aberrations recognized at birth or shortly after represent in other words only the tip of an iceberg. Structural chromosomal aberrations will lead to different syndromes that share some dysmorphic features. The phenotype may be variable even in the same chromosome s deletion or duplication, depending on its size and location. Cytogenetic analysis is therefore necessary to establish the exact diagnosis, in order to provide a genetic counseling.
18p- syndrome is not so frequent and is relatively rarely described at birth because of the minimal abnormalities visible at that time. About 60% of the children who carry this partial deletion are girls. The clinical picture of these patients varies from mild dysmorphism with long survival to death at the age of a few days 2, 3. One of the most frequent characteristics of the syndrome is mental retardation of variable degrees, followed by speech deficiency. No correlation was found between size of deletion and clinical condition 4. The phenotype is marked mainly by holoprosencephaly, brachycephaly, broad facies, blepharoptosis, tooth abnormalities, down turned corners of the mouth, broad neck, hand abnormalities, hypotonia. Cardiovascular, gastrointestinal, urogenital, endocrine, immunologic, hematopoietic systems may also be affected. Juvenile diabetes, autism, amenorrhea were also described to be associated with the deletion 18p - Figure 1. Early studies on the relationship between size of deletion and clinical phenotype in 18p- syndrome are still inconclusive.
The karyotype of the patient is shown in Figure 2, where a metaphase (see the arrows) and the selected pair 18, one normal and the second with deletion, can be seen. Therefore, we describe the karyotype as: 46,XX, del (18) (p11.31-11.32).
In the other affected child the cytogenetic analysis revealed a deletion on the q arm of chromosome 16, shown in Figure 3.The deletion of the long arm of chromosome 16 is characterized by developmental delay, craniofacial anomalies, failure to thrive, feeding difficulties, hypotonia and other disorders 5. The phenotype varies with the breakpoints. If the deletion involves more distal regions from 16q to 16q24.1 the dysmorphism is relatively mild, patients with deletions 16q21 have normal phenotype, but deletions in regions q24.2 and q24.3 are believed to be lethal 6, 7. The clinical picture of the second patient is presented in Figure 4.
The third patient was born with multiple congenital anomalies, affecting the head, face, heart, legs and muscles. His karyotype showed extremely large p arms of chromosome 15, Figure 5, but we could not establish the cause of this peculiar aspect. We considered the possibility that this could be an extreme variant of the short arm of chromosome 15. The likely mechanism explaining this variant chromosome involves amplification of rDNA sequences followed by inverted insertional translocation between the enlarged sister chromatids of the short arm of chromosome 15. Considering the size of the fragment it seems more likely that it belongs to another chromosome, but using only GTG-banding we could not establish its origin. Whether there is some duplication also remains uncertain.
Being located on the p arms, close to the centromere, any answer to this question is related to the size, polymorphism and variation of the centromeric G-band (8).
Figure 1: Clinical findings in patient 1 with deletion of the short arm of chromosome 18.
Figure 2: Metaphase and selected pair 18. One normal chromosome with its ideogram and the chromosome with the deletion added in order to show the loca [...]

Figure 3: Metaphase and selected pair 16. The arrows indicate the normal chromosome with its ideogram and the position of the deletion in the second c [...]
Figure 4: Clinical findings in patient 2 with deletion of the long arm of chromosome 16.

Figure 5: Metaphase and selected pair 15. One normal chromosome with its ideogram and the chromosome with extra genetic material on the p arms.
Structural chromosomal anomalies are not frequently seen at birth. Some of them may be lethal, but others may lead to mild phenotypes, which are not easily recognizable at birth or immediately after. Thus, even in the presence of some mild dysmorphic features, the pediatrician should keep in mind that a cytogenetic investigation might be needed, as it could facilitate the diagnosis.
Further documentation of phenotypic abnormalities in subjects with chromosomal aberrations is needed in order to understand the relationship between them and the etiology as well.

1. The International Human Genome Mapping Consortium: A physical map of the human genome. Nature, 2001, 409: 934-941
2. Knoll J H M, Nichols D, Magenis R E: Somatic cell hybrid deletion map of chromosome 18. Am. J. Med. Genet., 1989, 32: 285-290
3. Schinzel A: Ed. Catalogue of unbalanced chromosome aberrations in man. de Gruyter, New York, Berlin, 1984
4. Wilson G N: Karyotype-phenotype controversy: genetic and molecular implications of alternative hypothesis. Am. J. Med. Genet., 1990, 36: 500-505
5. Casamassima A C, Klein R M, et al.: Deletion of chromosome 16q with prolonged survival and unusual radiographic manifestation, Am. J. Med. Genet., 1990, 37: 504-509
6. Fujiwara M, Yoshimoto T, Morita Y, Kamada M: Interstitial deletion of chromosome 16q: 16q22 is critical for 16q syndrome. Am. J. Med. Genet., 1992, 43: 561-564
7. Trautmann U, Pfeiffer R A, Seufert-Satomi, Tietze H U: Simultaneous de novo interstitial deletion of 16q21 and intercalary duplication of 19q in a retarded infant with minor dysmorphic features. J. Med. Genet., 1993, 30: 330-331
8. Piccini I, Ballarati L, Bassi C, Marozzi A, Ginelli E, Meneveri R: Molecular analysis of the p arm of human acrocentric chromosomes. HGM, 2001

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